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CN-121974926-A - Process for the preparation of 2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane

CN121974926ACN 121974926 ACN121974926 ACN 121974926ACN-121974926-A

Abstract

The present invention relates to a process for the preparation of (±) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane of formula (I), any individual enantiomer thereof or any non-racemic mixture thereof, comprising the steps of (a) reacting (±) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane of formula (II), any individual enantiomer thereof or any non-racemic mixture thereof with a 2-methylbenzyl compound of formula (III) wherein X is a leaving group in the presence of at least one base capable of forming water or a C 1 -C 4 alkyl alcohol under reaction conditions and at least one inert organic solvent, and (b) simultaneously removing water, a C 1 -C 4 alkyl alcohol or any mixture thereof from the reaction mixture.

Inventors

  • S. Benson
  • M. Reick
  • B. WOLF
  • R. Getze
  • J. GEBHARDT
  • H. cross

Assignees

  • 巴斯夫农业公司

Dates

Publication Date
20260505
Application Date
20170907
Priority Date
20160919

Claims (15)

  1. 1. A process for the preparation of (+ -) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane of formula (I), any of its individual enantiomers or any non-racemic mixture thereof, The method comprises the following steps: (a) Reacting (±) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane of formula (II), either its individual enantiomer or any non-racemic mixture thereof, with a 2-methylbenzyl compound of formula (III) in the presence of at least one base capable of forming water or a C 1 -C 4 alkyl alcohol under reaction conditions and at least one inert organic solvent Wherein X is a leaving group, and (B) Water, C 1 -C 4 alkyl alcohol, or any mixture thereof is simultaneously removed from the reaction mixture.
  2. 2. The process according to claim 1, wherein in step (b) water, C 1 -C 4 alkyl alcohol or any mixture thereof is removed from the reaction mixture by azeotropic distillation.
  3. 3. A method according to claim 1 or 2, wherein step (b) comprises the steps of: (b 1.1) removing water, C 1 -C 4 alkyl alcohol or any mixture thereof from the reaction mixture as an azeotrope formed from the inert organic solvent and water, C 1 -C 4 alkyl alcohol or any mixture thereof, and (B 1.2) adding an inert organic solvent or a mixture comprising said inert organic solvent and having a lower concentration of water, C 1 -C 4 alkyl alcohol or any mixture thereof than the azeotrope to the reaction mixture during the reaction.
  4. 4. A process according to any one of claims 1 to 3, wherein in step (b) or (b 1.1) water, a C 1 -C 4 alkyl alcohol or any mixture thereof is removed simultaneously and continuously from the reaction mixture.
  5. 5. A process according to claim 1 to 4, wherein X is selected from halogen, an oxygen-linked leaving group and an ammonium group of formula (IV) N(R 1 )(R 2 )(R 3 ) + Y - (IV) Wherein R 1 、R 2 and R 3 are each independently selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and C 6 -C 20 aryl, and Y - is selected from halide, hydroxide, C 1 -C 4 alkylsulfonate and C 6 -C 20 arylsulfonate.
  6. 6. The method according to any one of claims 1-5, wherein X is selected from halogen.
  7. 7. The process according to any one of claims 1-6, wherein the base is selected from the group consisting of alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali and alkaline earth metal bicarbonates, alkali and alkaline earth metal oxides, alkali and alkaline earth metal C 1 -C 4 alkoxides, and any combination thereof.
  8. 8. The process according to any one of claims 1 to 7, wherein the base is selected from alkali metal hydroxides.
  9. 9. The process according to any one of claims 1 to 8, wherein the inert organic solvent is capable of forming an azeotrope with water, a C 1 -C 4 alkyl alcohol, or any mixture thereof.
  10. 10. The process according to any one of claims 1 to 9, wherein the inert organic solvent is selected from hydrocarbons.
  11. 11. The process according to any one of claims 1-10, wherein the inert organic solvent is selected from the group consisting of aliphatic hydrocarbons, cycloaliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, and any combination thereof.
  12. 12. The process according to any one of claims 1 to 11, wherein the inert organic solvent is selected from aromatic hydrocarbons.
  13. 13. The process according to any one of claims 1 to 12, wherein the inert organic solvent is toluene.
  14. 14. The process according to any one of claims 1 to 13, wherein the 2-methylbenzyl compound of formula (III) is a 2-methylbenzyl chloride of formula (IIIa): 。
  15. 15. A process for preventing or reducing the formation of deposits on the interior of a reactor, wherein the preparation of (±) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane, either its individual enantiomer or any non-racemic mixture thereof of formula (I) is carried out by reacting (±) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane, either its individual enantiomer or any non-racemic mixture thereof of formula (II) with a 2-methylbenzyl compound of formula (III): wherein X is a leaving group and wherein, The method comprises the following steps: (a) Carrying out the reaction of (±) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane of formula (II), either its individual enantiomers or any non-racemic mixture thereof, with a 2-methylbenzyl compound of formula (III) in the presence of at least one base capable of forming water or a C 1 -C 4 alkyl alcohol under reaction conditions and at least one inert organic solvent, and (B) Water, C 1 -C 4 alkyl alcohol, or any mixture thereof is simultaneously removed from the reaction mixture.

Description

Process for the preparation of 2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane The application is a divisional application of Chinese patent application with the application date of 2017, 9-7, the application number of 201780057210.6 and the name of 'a method for preparing 2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane'. The present invention relates to a process for the preparation of (±) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane, any of its individual enantiomers or any of its non-racemic mixtures of formula (I) by reacting (±) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane, any of its individual enantiomers or any of its non-racemic mixtures of formula (II) with a 2-methylbenzyl compound of formula (III) in the presence of a base and an organic solvent. The racemic mixture (±) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane is a known herbicidal compound which has been developed for rice. It is described in THE PESTICIDE Manual, 14 th edition, editions C.D.S. Tomlin, british Crop Production Council,2006, 157, pages 195-196, commonly known under the name Cycloheptane (CINMETHYLIN), its IUPAC name (1 RS,2SR,4 SR) -1, 4-epoxy-pair-2-Yl 2-methylbenzyl ether with the chemical abstract name of external- (±) -1-methyl-4- (1-methylethyl) -2- [ (2-methylphenyl) methoxy ] -7-oxabicyclo [2.2.1] heptane. The racemic mixture (±) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane (also referred to herein as the "exo- (±) -isomer", CAS RN 87818-31-3) contained equal parts of the two enantiomers (+) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane (also referred to herein as the "exo- (+) -isomer", CAS RN 87818-61-9) and (-) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane (also referred to herein as the "exo- (-) -isomer", CAS RN 87819-60-1). EP 0 081893 A2 describes the preparation of (+ -) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane and its exo- (+) -isomers and exo- (-) -isomers by reacting (+ -) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane with 2-methylbenzyl chloride in the presence of sodium hydride as base and dimethylformamide as organic solvent (see examples 29, 34, 35 and 62). The use of sodium hydride as a base and dimethylformamide as an organic solvent in the preparation of (±) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane by reacting (±) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane with 2-methylbenzyl chloride is also described in US 4,487,945 (see embodiment 48), US 4,542,244 (see embodiment 219) and US 4,670,041 (see embodiment 219). Furthermore, the preparation of the exo- (-) -isomer by reacting (-) -2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane with 2-methylbenzyl chloride in any of the above references is carried out in the presence of sodium hydride as base and N, N-dimethylacetamide as organic solvent (see U.S. Pat. No. 3,4,487,945, embodiment 46; U.S. Pat. No. 4,542,244, embodiment 218 and U.S. Pat. No. 4,670,041, embodiment 218). CN 101602770A describes a three-step synthesis for the preparation of cycloheptyl ether. In steps 1 and 2 terpinen-4-ol is converted to the corresponding 1, 2-epoxide which is then isomerized to give the 1, 2-epoxide isomerisation product. In the final step 3, the cycloheptyl ether is obtained by condensing the 1, 2-epoxide isomerisation product in the presence of various combinations of base and organic solvents (see examples 1,2,3, 8 and 9: sodium hydroxide/ethyl acetate; examples 4 and 5: sodium amide/dichloromethane; example 6: sodium hydride/benzene and example 7: sodium hydride/toluene). However, alkali metal hydrides such as sodium hydride or amides such as sodium amide are dangerously reactive in the presence of small amounts of oxygen or moisture. Such reactions may lead to the formation of hazardous gases such as hydrogen (H 2) or ammonia (NH 3). Thus, appropriate care and precautions should be taken during handling and storage of these materials and during the above-described process for preparing (+ -) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane. Thus, specific safety measures are required during the course of the reaction, such as an inert gas atmosphere (e.g. nitrogen), proper cooling, removal of gases such as H 2 or NH 3 and dilution. In addition, alkali metal hydroxides such as sodium hydroxide are bases known in the saponification of esters. Thus, the combined use of sodium hydroxide and ethyl acetate in the synthesis of (±) -2-exo- (2-methylbenzyloxy) -1-methyl-4-isopropyl-7-oxabicyclo [2.2.1] heptane (see examples 1, 2, 3, 8 and 9 of CN101602770 a) can result in the hydrolysis of the solvent ethyl acetate. This means the formation of relatively large amounts of u